NOTE: FOLLOWING REFERENCES WERE COLLECTED SINCE DIAGNOSIS IN 1967.
FIRST research published proving remyelination as a natural process is, Bunge Mary B, Bunge RP and Ris H (1961), Ultrastructural Study of Remyelination in an Experimental Lesion in Adult Cat Spinal Cord, in the Journal of Biophysics, Biochemistry and Cytology, Volume 10, pages 67-94, 1961, NOTE J Cell Biol since 1962.
The first sign of myelin repair was observed after 19 days; by 64 days all nerve damage was thinly repaired. p81- authors observe that reformed myelin resembles that which is formed in normal development. p81 “The neurological condition of the experimental animal (adult cat) begins to improve at a time when remyelination begins and has returned to normal by the time most axons are at least partly remyelinated.”
[EM I found this research after diagnosis in 1967, when I was working at the Veterinary College in Guelph Ontario. Veterinary researchers assured me that adult cats and humans are in the same biological class – large mammals, and that humans should be able to experience healing as did the adult cats in this study. Being a farm kid, I knew that injured animals recover by always pushing to their limit, and, getting lots of sleep.]
Raine CS and Bornstein MB, EAE: A Light and Electron Microscopy Study of Remyelination and Sclerosis in Vitro. J Neuropath Exp Neurol 29:552, 1970. total demyelination in living mice embryo tissue cultures … Tissue fragments began to remyelinate after 8 -10 days and process was well advanced by 18 days. By three weeks, almost total remyelination.
Hirano A, Levine S and Zimmerman HM, Remyelination in the Central Nervous System after Cyanide Intoxication. J Neuropath Exp Neurol 27:234-245, 1968. By one week after demyelination [in adult rats] we observed remyelination … recently several fine structural studies have established this phenomenon beyond reasonable doubt. p235
Gledhill R, Harrison BM, MacDonald WI, Demyelination and Remyelination After Acute Spinal Cord Compression. Exp Neurol 38:472-487, 1973. Remyelination in cats commenced 7-21 days after demyelination and majority of demyelinated fibres showed evidence of remyelination by 1month.
Evans, Sir Charles Lovatt (1956)Principles of Human Physiology 12th Edition, J&A Churchill Ltd. London. – p180 generate myelin – assume control (movement) – abnormal sensations , re-education – p719 … there is a migration of certain tissue cells , viz fibroblasts and histiocytes to the affected place; later there is often a further emigration from the blood of histiocytes and of lymphocytes. Of these various cells, the polymorphonuclear leucocytes and the histiocytes are phagocytic and help to remove invading particles or organisms, and also, later to remove the tissue injured by the primary lesion. As soon as this is effected, repair of the injured tissue occurs by proliferation of the fibroblasts and the epithelium, while the leucocytes are destroyed by macrophages.
P719 The four cardinal symptoms of inflammation, namely, rubor, calor, turgor, and dolor, which have been described for centuries as typical of this condition, naturally leave out of account the phenomenon of phagocytosis (ingestion of bacteria and particles) around the seat of injury with the object of removing injured tissue, of destroying micro-organisms, of protecting the body from general infection, and of preparing the way for reintegration of new tissue.
Patten Bradley M, Foundations of Embryology. McGraw-Hill Book Company, Inc. New York London Toronto 1958. – Cerebrospinal Conduction Paths. p351 Phylogenetically these [cerebrospinal] conduction paths in the peripheral part of the cord increase in conspicuousness concomitantly with the increasing extent to which the brain assumes a co-ordinating control over the basic reflexes which constitute the primary function of the cord. Paraphrase … the ‘white matter’ or myelin, in the motor part of the cord, develops as the brain assumes control over basic reflexes.
[EM What Bradley says in plain language is – since movement promotes creation of myelin – Sooo it seems reasonable to me to believe that movement must also promote re – myelination.]
Feigin I & Popoff N, Regeneration of Myelin in Multiple Sclerosis. Neurol 6:364-372, 1966. Nerve fibers myelinated by peripheral myelin were found within plaques in five cases of Multiple Sclerosis. These fibers were present singly, in small clusters, and, occasionally, in large groups. p364. … did not exceed 10% of the number thought to be demyelinated … found only within plaques, not in normal tissues … The five cases in which regenerative myelin was recognized, differ from eighteen other cases of Multiple Sclerosis available for study in that four were women, while men predominated in the rest. [80% – 4/5 women and 6% – 1/18 men showed remyelination- em] …remissions observed in many cases where no remyelination observed … The regeneration of myelin may play a role in the clinical remissions of Multiple Sclerosis, but other factors appear to be more important. If ways were found to enhance the regeneration observed in this study, a clinically useful purpose might be served.
[EM … Also observed TOO FEW WOMEN patients available for scientific study group.]
Bunge Mary B, Bunge RP and Edith R Peterson, The Onset of synapse formation in spinal cord cultures as studied by electron microscope. Br Res 6: 728-749, 1967. Demonstrates close correlation between the initiation of synaptic formation and the onset of functional synaptic networks. [EM NOTE formation of synapses related to function ie movement speeds healing …]
Millar JHD, Multiple Sclerosis: A Disease Acquired in Childhood. Charles C. Thomas. Springfield, Illinois, U.S.A. IF … normal turnover of myelin during development, then mechanisms must exist both to demyelinate and remyelinate axons 1971. p45.
Harrison BM, McDonald WI and Ochoa J, Remyelination in Central Diphtheria Toxin Lesion. J Neurol Sci 17:293-302, 1972. … even the limited amount of remyelination observed may be sufficient to restore transmission. Although conduction would still be slow in the thinly myelinated fibres, the return of the ability to conduct at all is clearly a necessary first step in the recovery of function in damaged pathways. p301.
Rasminsky M and Sears TA, Internodal Conduction in Undissected Demyelinated Nerve Fibres. J. Physiol 227:323-350, 1972. – intracellular sodium accumulation is also offered as the explanation for (affected activity) seen in demyelinated fibres – position of nodes inferred from assumption that nodes are the only sites of inward membrane current [NOTE em … steroids affect the balance of sodium and potassium (mineralocorticoids) vital for potential difference needed for signal transmission and slow repair and recovery .. ]
– intracellular sodium accumulation is also offered as the explanation for the post-tetanic depression seen in demyelinated fibres p324
– position of nodes inferred from assumption that nodes are the only sites of inward membrane current p329
Koles ZJ and Rasminsky M (1972) A Computer Simulation of Conduction in Demyelinated Nerve Fibres. J Physiol 227:351-364.
– possible that age may play part in extent of remyelination [EM … no one links extent of movement to repair of myelin!]
– in remyelinating animal axons more are myelinated at once [EM … because animals keep trying to move whereas humans are told recovery is impossible.]
– propagation continues until thickness less than 2.7 % of normal – blocked by increase in sodium [EM .. released from damaged myelin.]p351
therefore 2.7 % myelin thickness sufficient
Smith R.S. and Koles Z.J. (1970) Myelinated Nerve Fibres:Smith R.S. and Koles Z.J. (1970) Myelinated Nerve Fibres: Computed Effect of Myelin Thickness on Conduction Velocity. Am. J. Phys. 219:1256-1258.
“… model suggests that the conduction can proceed across an internode if the entire internode is divested of all but three bilayers of compact myelin, if the distal two ninths of the internode is divested of all but one Schwann cell membrane, or if the axon is completely bare over 1/9 of the internode.
These quantitative findings may be of some relevance in relation to human demyelinating diseases. The poor correlation between clinical and pathological findings in patients with ms is well known (see Makay & Hirano(1967) and Namerow & Thompson (1969). The computations suggest that extremely thin myelinated axons may be capable of conducting impulses; the histological methods used in light microscopic neuropathology are inadequate to distinguish between thinly myelinated axons which would, and bare axons which could not, conduct impulses. It thus seems entirely conceivable that in some cases impulses can in fact be conducted through most fibres in a plaque of demyelination; this would explain hitherto puzzling failure of some plaques in patients with ms to give rise to symptoms.”
Ghatak NR, A Hirano, H Lijtmaer and HA Zimmerman, Asymptomatic Demyelinated Plaques in the Spinal Cord. Arch Neurol 30:484-486, 1974. Poor correlation between lesions and clinical symptoms in MS … extent of lesions in MS frequently far greater than would be anticipated from the clinical assessment.
Ghatak NR, Leshner RT, Price AC and Felton WL, Remyelination in the human nervous system. J Neuropath Exp Neurol 48(5):507-518, 1989. Thinly myelinated axons play role in continuous conduction … flu like … substantial remyelination possible in MS. Remyelination is often considered as a possible explanation for remission in MS. To our knowledge, clinically significant functional recovery as a result of remyelination has not been documented in humans …
Raine CS, Multiple sclerosis: a pivotal role for the T cell in lesion development. Neuropath & App Neurobiol 17: 265-274, 1991. – counteraction of the inflammatory response in the CNS appears to lead to cessation of the immune mediated disease and encouragement of remyelination – myelin debris – oligodendrites not target, myelin membrane itself – entire lesions remyelinate.
BDJ Miller, K Asakura and M Rodriguez, Experimental Strategies to Promote Central Nervous System Remyelination in Multiple Sclerosis: Insights Gained From the Theiler’s Virus Model System. Mini-Review. J Neurosci Res 41:291-296, 1995. Remyelination is a normal physiological response to myelin damage … central issue in CNS repair in MS is not whether remyelination occurs, but rather can we determine therapies to stimulate myelin repair. [EM – encourage movement, and STOP saying there is no repair!]
Sandyk R, Chronic Relapsing multiple sclerosis: a case of rapid recovery by application of weak electromagnetic fields. Int J Neurosc Jun 82(3-4):223-42, 1995. Neurocommunication Research Laboratories, Danbury CT 069111 USA. … application of 2 successive treatments of pulsed electromagnetic fields …
patient experienced immediate improvement in symptoms, most dramatically balance, gait, speech and level of energy …
Report points to the unique capacity of externally applied pT range EMF’s in the symptomatic treatment of MS … indicates a lack of an association between the extent of demyelinating plaques on MRI scan and rate and extent of recovery in response to EMFs, and supports the notion that dysfunction of synaptic conductivity due to neurotransmitter deficiency … contributes more significantly to the development of MS symptoms than the process of demyelination which clinically seems to represent an epiphenomenon (secondary happening) of the disease.[NOTE epiphenomenon def – secondary happening, dependent or subject to – an event.
in other words: lack of nerve connections is worse than damage to myelin !! nerve connections are reformed with use, that is, with thought and movement. ]
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Silberberg D.H. (1970) Recent Concepts of Etiology. Mod. Treat. 7:882-886.– SEASONAL PATTERNS OF ACUTE EXACERBATIONS – ABORTIVE ATTEMPTS AT REMYELINATION OCCUR gliosis (- def- excess astroglia in damaged areas of CNS) resulting from astroglial proliferation following demyelination may retard remyelination – corticosteroids found to offer only questionable benefits …
Gledhill RF (1973) Pattern of Remyelination in the CNS. Nature 244:443-444. – myelin destruction followed by remyelination in 3rd week – CATS- known prerequisites for saltatory conduction present in remyelinated fibers – segments shorter than undemyelinated SCHWANN cells migrating in spinal cord & forming myelin around central axons
Lampert P.W. (1978) Autoimmune and Virus-Induced Demyelinating Diseases. Am. J. Path. 91:176-197. – CNS single oligodendrocyte is connected to many myelin segments by long cytoplasmic projections – regeneration in remission limited to margin of demyelinated plaques – abortive remyelination …
[EM … abortive simply means repair seems incomplete … research has proven that we actually need as little as 3% of normal myelin thickness to function See RASMINSKY AND SEARS above.]
Prog Neurobiol. 2013 Feb-Mar;101-102:46-64. doi: 10.1016/j.pneurobio.2012.11.003. Epub 2012 Nov 29.
Viral models of multiple sclerosis: neurodegeneration and demyelination in mice infected with Theiler’s virus. Mecha M, Carrillo-Salinas FJ, Mestre L, Feliú A, Guaza C. Neuroimmunology Group, Functional and System Neurobiology Department, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Multiple sclerosis (MS) is a complex inflammatory disease of unknown etiology that affects the central nervous system (CNS) white matter, and for which no effective cure exists. Indeed, whether the primary event in MS pathology affects myelin or axons of the CNS remains unclear. Animal models are necessary to identify the immunopathological mechanisms involved in MS and to develop novel therapeutic and reparative approaches. Specifically, viral models of chronic demyelination and axonal damage have been used to study the contribution of viruses in human MS, and they have led to important breakthroughs in our understanding of MS pathology. The Theiler’s murine encephalomyelitis virus (TMEV) model is one of the most commonly used MS models, although other viral models are also used, including neurotropic strains of mouse hepatitis virus (MHV) that induce chronic inflammatory demyelination with similar histological features to those observed in MS. This review will discuss the immunopathological mechanisms involved in TMEV-induced demyelinating disease (TMEV-IDD). The TMEV model reproduces a chronic progressive disease due to the persistence of the virus for the entire lifespan in susceptible mice. The evolution and significance of the axonal damage and neuroinflammation, the importance of epitope [definition: the part of an antigen molecule to which an antibody attaches itself] spread from viral to myelin epitopes, the presence of abortive remyelination and the existence of a brain pathology in addition to the classical spinal cord demyelination, are some of the findings that will be discussed in the context of this TMEV-IDD model. Despite their limitations, viral models remain an important tool to study the etiology of MS, and to understand the clinical and pathological variability associated with this disease.
Brain Res. 1998 Jan 26;782(1-2):126-35. Spontaneous long-term remyelination after traumatic spinal cord injury in rats. Salgado-Ceballos H, Guizar-Sahagun G, Feria-Velasco A, Grijalva I, Espitia L, Ibarra A, Madrazo I. Unit of Medical Research in Neurological Diseases, Instituto Mexicano del Seguro Social, México, DF, México.
The capability of the central nervous system to remyelinate axons after a lesion has been well documented, even though it had been described as an abortive and incomplete process. At present there are no long-term morphometric studies to assess the spinal cord (S.C.) remyelinative capability.
… Remyelination was mainly achieved because of Schwann cells. The proportion of small fibers (diameter = 0.5 micron or less) considered as axon collaterals, increased from 18.45% at 1 month to 27.66% a year after the contusion …. results suggest that remyelination is not an abortive phenomenon but in fact a slow process occurring parallel to other tissue plastic phenomena, such as the emission of axon collaterals [EM such as dendrites.]
Brain Res. 1995 Feb 20;672(1-2):159-69. Phenotypic and cell cycle properties of human oligodendrocytes in vitro. Prabhakar S, D’Souza S, Antel JP, McLaurin J, Schipper HM, Wang E. Department of Neurology and Neurosurgery, McGill University, Montreal, Que., Canada.
The remyelination, albeit limited, which occurs at the lesion sites in the central nervous in multiple sclerosis has been attributed to both myelin production by previously myelinating cells and to precursor cells which mature into myelin-producing cells. Oligodendrocyte (OL) number may be increased at the periphery of the lesions … our results suggest that a small number of phenotypic ‘pre-oligodendrocytes’ can be derived from the adult human CNS …
Neurosurgery. 1994 Dec;35(6):1112-20. Experimental syringomyelia in the rabbit: an ultrastructural study of the spinal cord tissue. Chakrabortty S, Tamaki N, Ehara K, Ide C. Department of Neurosurgery, Kobe University School of Medicine, Japan.
Hydrosyringomyelia was produced experimentally by the injection of kaolin into the cisterna magna of the rabbit, and the ultrastructural changes of the spinal cord surrounding the syrinx were investigated 2, 4, and 6 weeks after injection by transmission electron microscopy. The ependyma at the ventral part of the central canal was flat and stretched, whereas, in the dorsal part, it was split, and the syrinx extended through the dorsal median plane in most animals. Extracellular edema was found in the subependymal white matter and in and around the posterior median septum. Many nerve fibers surrounding the syrinx were in varying stages of axonal degeneration. Myelin sheaths were split, thinned, and completely lost in many nerve fibers. In some fibers, the axons were totally lost, leaving the myelin sheaths as empty tubes. Astrocytic processes containing a large number of glial filaments covered the nerve fibers adjacent to the syrinx and partially replaced the edematous area. The perivascular spaces were enlarged, especially near the syrinx and in the dorsal white matter. Oligodendrocytes remained undamaged, and the remyelination by oligodendrocytic processes was seen on some denuded axons. Sometimes, this further remyelination was abortive, especially where the edema was severe. The ultrastructural changes of the neural tissue and their sequences were identical, in most respects, to those of hydrocephalus and noncommunicating syringomyelia. The oligodendrocytic remyelination with ongoing demyelination found in this model has many similarities to those in experimental hydrocephalus.
Dev Neurosci. 1989;11(2):112-7. Review of the morphological aspects of remyelination. Hirano A. Montefiore Medical Center, Bronx, N.Y.
The advent of proper preparative and experimental techniques has allowed us to investigate the central nervous system myelin both in the normal animal and during remyelination. Remyelination often follows the pattern of myelination during development but, in addition, shows certain variations such as participation of Schwann cells, and is apparently always incomplete. Observations in multiple sclerosis indicate that the abortive remyelination which occurs in the demyelinated plaque is similar to that seen in the experimental animals.
Smith KJ WF Blakemore and WI McDonald (1979) Central remyelination restores conduction. Nature 280:395-396
– we have found that secure conduction is restored with remyelination. (cats) Remyelination had begun by 14 days.
Brain Volume 128, Issue 3 Pp. 528 – 539 Inflammation stimulates remyelination in areas of chronic demyelination A. K. Foote , W. F. Blakemore DOI: http://dx.doi.org/10.1093/brain/awh417 528-539 First published online: 7 February 2005
A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences…. taipei rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis:
J Neuropathol Exp Neurol. 2013 Jan;72(1):42-52. doi: 10.1097/NEN.0b013e31827bced3. Diffusely abnormal white matter DAWM in multiple sclerosis: further histologic studies provide evidence for a primary lipid abnormality with neurodegeneration. Laule C, Pavlova V, Leung E, Zhao G, MacKay AL, Kozlowski P, Traboulsee AL, Li DK, Moore GR. Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. email@example.com[EM … abnormality or STAGE OF REMYELINATION ???]
Although multiple sclerosis (MS) lesions have been studied extensively using histology and magnetic resonance imaging (MRI), little is known about diffusely abnormal white matter (DAWM) … regions with reduced mild MRI hyperintensity and ill-defined boundaries … further histologic characterization is warranted. The MRI data were collected on 14 formalin-fixed MS brain samples … diffusely abnormal white matter lipid and protein reductions occurred independently. These findings suggest a primary lipid abnormality in DAWM that exceeds protein loss and is accompanied by axonal degeneration. These phenomena may be important in MS pathogenesis and disease progression, which is prominent in individuals with DAWM.
[EM “diffusely abnormal white matter” … IN DEPTH review of electron microscope studies of real tissue rather than MRI studies that reveal the speed of electron spin … reveals FACT that what is interpreted as abnormality is a stage in myelin repair. ALSO repeated movement is CRITICAL to direct remyelination … just as practice is essential for learning a skill.]